ABSTRACT Alzheimer's disease (AD) is one of the largest global public health crises facing us today, yet there are no effective therapies available to prevent, delay, or slow AD progression. Dominant approaches based on a set of prevailing core hypotheses about druggable pathways and targets have failed. Therefore, there is a need for novel and alternative pathways distinct from those pursued over the past two decades. Our strategy is to target a particular form of dysregulated neuroinflammation, injurious proinflammatory cytokine overproduction that is a key contributor to synaptic dysfunction, neurodegeneration and cognitive decline in diverse neurodegenerative diseases. We seek Fast-Track SBIR funding for a first-in-human (FIH) study of MW01-2-151SRM (=MW151), a novel, CNS-penetrant, orally bioavailable, small molecule drug candidate that selectively suppresses stressor- induced proinflammatory cytokine overproduction. MW151 ameliorates synaptic damage and cognitive impairment at low doses in diverse animal models where proinflammatory cytokine dysregulation is established as a contributor to neurologic injury or susceptibility to neurologic injury. MW151 is chemically and metabolically stabile, has no liabilities in investigational new drug (IND)-enabling safety pharmacology and toxicology screens following ICH/FDA guidance. These include respiratory and cardiovascular safety pharmacology screens, rat and dog 28-day repeat administration toxicology studies, and genotox analyses. Further, a MW151 analog developed for the more demanding i.v. route of administration has been substantially de-risked in a phase 1b clinical trial. Overall, MW151 is a highly de-risked and promising candidate for clinical development as an oral formulation for the treatment of AD or related disorders. Aim 1: Prepare regulatory and other processes for a FIH SAD trial. The tasks include preparation and regulatory approval of required clinical trial documents, and the validation of methods for measurement of MW151 in human plasma. Aim 2: Conduct a single ascending dose (SAD) phase 1a trial of MW151. The SAD study will determine safety and tolerability and maximum tolerated dose of MW151 as well as its pharmacokinetic (PK) profile in a SAD paradigm in healthy adult volunteers. Plasma cytokine levels will be measured to provide baseline data for a future exploratory pharmacodynamic (PD) endpoint in phase 1b/2a clinical trials. Aim 3: Prepare regulatory and other processes for a multiple ascending dose (MAD) phase 1b trial. We will design a multiple ascending dose (MAD) clinical study of MW151 in healthy volunteers, including a cohort of elderly healthy subjects. This project will advance clinical development of a promising drug candidate that could have disease-modifying effects not only in AD but also in a number of other CNS disorders where proinflammatory cytokine dysregulation is part of the pathophysiology progression mechanism.